Gamma interferon (IFN3) is an essential cytokine for mediation of immune functions that are critical for surveillance against infections and cancer. Important aspects of innate immunity, adaptive immunity, macrophage activation, natural killer cell activity, helper T cell responses, as well as cytotoxic T cell responses are all critically modulated by IFN3. We have developed small peptide mimetics of IFN3. The IFN3 mimetics exhibit antiviral activity against a variety of viruses including amelioration of the lethal effects of the poxvirus vaccinia in mice under conditions where intact IFN3 is ineffective because of anti- IFN proteins produced by poxviruses. The activating effects of IFN3 are suppressed by proteins called suppressors of cytokine signaling (SOCS), of which SOCS-1 is an important member. We have developed a small molecule SOCS-1 antagonist. In this renewal, we propose to study the interaction between IFN3, IFN3 mimetics, and SOCS-1 antagonist as per AIMs below to positively regulate the IFN responses of cells of the immune system and enhancement of protection of mice against vaccinia and ectromelia viruses with a view toward an IFN and SOCS-1 antagonist drug against smallpox. We hypothesize that our small peptide IFN mimetics and SOSC-1 antagonist represent novel antivirals against lethal poxvirus infections. 1. Protection of mice against lethal vaccinia virus infections by IFN mimetics. Effect of SOCS-1 antagonist on protection. 2. Compare intraperitoneal versus oral administration of IFN mimetic peptides for their relative ability to protect mice against lethal vaccinia virus infection. Effect of SOCS-1 antagonist. 3. Protection of mice against lethal ectromelia virus infection by IFN mimetics and SOCS-1 antagonist. 4. Protection of mice against superlethal ectromelia virus encoding the interleukin-4 (IL-4) gene by IFN mimetics and SOCS-1 antagonist. 5. Determine immunological aspects of treatment of mice with IFN mimetics. Effect of SOCS-1 antagonist. PUBLIC HEALTH RELEVENCE: Our interferon mimetic is a novel therapeutic for treating viral and other infectious diseases. The SOCS-1 antagonist should provide a new paradigm to boosting the immune system against infections and cancer.